Cystic fibrosis affect 70,000 children and adults worldwide (Cystic fibrosis foundation). Although more than 1,400 different mutations can lead to defects in CFTR, the most common mutation is a deletion of phenylalamine residue at position 508 of the protein (DF508 CFTR). This mutation is responsible for more than 90 percent of CF cases worldwide.
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations of the CF transmembrane conductance regulator (CFTR) gene, which encodes a transmembrane protein present on a variety of cell types and organelles. The most common mutation of the CFTR gene is a 3-base-pair deletion resulting in the deletion of phenylalanine at position 508, known as the F508del CFTR mutation. While CF is classically characterized by the presence of pancreatic insufficiency and recurrent lung infections in infants, a wide clinical spectrum has been identified in adults. Chronic bacterial infection of the airways, thickened airway mucous, and bronchiectasis characterizes the CF lung. The excess of mucus is largely caused by the influx of neutrophils, attracted to the site by the increased expression of chemokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8), by bacterial products and inflammatory cytokines.
For instance, IL-8, produced by macrophages, epithelial cells, and fibroblasts, is a potent chemokine and activator for human neutrophils and is considered to be an important proinflammatory cytokine in the pathogenesis of CF (E. Puchelle, S. De Bentzmann, C. Hubeau, J. Jacquot, and D. Gaillard, “Mechanisms involved in cystic fibrosis airway inflammation,” Pediatric Pulmonology, vol. 32, no. 23, pp. 143-145, 2001). IL-8 is induced transcriptionally by a wide variety of stimuli including tumor necrosis factor-alpha (TNF-α), hyperosmotic shock, and bacterial products. CF causes a massive pro-inflammatory phenotype in the lung, which manifests in the airway by high levels of IL-8 and other pro-inflammatory cytokines and chemokines (Bhattacharyya S. et al., J Biol Chem. 2011 Apr. 1; 286(13):11604-11615). IL8 thus appears to be a major inflammatory cytokine playing a key role in CF, in particular nasal and bronchial CF symptoms.
Progressive lung disease in cystic fibrosis (CF) is largely due to persistent inflammation characterized by an abundance of activated neutrophils. The influx of neutrophils into CF airways has been traditionally thought to be a response to chronic infection with bacteria. However, recent bronchoalveolar lavage (BAL) studies have documented elevated levels of neutrophils in the lower airways of some infants with CF even in the absence of detectable infection. These observations are consistent with the hypothesis that inflammation is abnormally regulated in CF airways. Attention has been focused on interleukin IL-8, a chemokine that accounts for most of the neutrophil chemoattractant activity of CF sputum and is repeatedly found in elevated concentrations in the airways of patients with CF. A potentially major source of IL-8 in the airways is the respiratory epithelium. Since the respiratory epithelium also manifests the most important phenotypic abnormality of CF, CF airway epithelial cells overproduce IL-8, and this is linked to abnormal function of the cystic fibrosis transmembrane regulator (CFTR). IL-8 production in CF and non-CF primary nasal epithelial cell cultures at baseline and after stimulation with tumor necrosis factor-α (TNF-α) or infection by respiratory syncytial virus (RSV) were used as IL-8 models (Nasal epithelium has the same ion transport abnormalities as lower airway epithelium in CF).
Treatments for CF disease typically involve antibiotics, anti-inflammatory drugs, bronchodilators, and chest physiotherapy to help fight infection, neutrophilic inflammation and obstruction and clear the airways. The goal is thus to maintain the lung functions as near to normal by controlling respiratory infection and clearing airways of mucus. Nevertheless, the persistent, viscous and toxic nature of airway secretions in cystic fibrosis disease still leads to progressive deterioration of lung function. Despite its serious clinical consequences, there is no approved therapy for the treatment of CF except ivacaftor (Kalydeco® by Vertex) recently registered in the US and under review in Europe as a cystic fibrosis trans membrane conductance regulator (CFTR) potentiator. Ivacaftor is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have a G551 D mutation in the CFTR gene. Ivacaftor is only authorized to treat a small sub-set of CF patients, those who have the G551 D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene and just 4% of CF patients are believed to have this mutation. In addition, sinus related pathology is poorly specifically treated during CF.
No treatment of cystic fibrosis that significantly improves quality of life of patients over a longer period is available so far.
Accordingly, there is a need for alternative or additional treatments for CF and any complication thereof.
7-amino-4,5,6-triethoxy-3-(4-methoxy-6-methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-3H-isobenzofuran-1-one or tritoqualine is a drug, previously formulated in 100 mg tablets and sold in Europe for the treatment of allergy. Tritoqualine is not a pure product but is available as a mixture of isomers.
The disclosed mechanism of action of tritoqualine relates to the inhibition of histamine biosynthesis. More specifically, tritoqualine is an inhibitor of the enzyme histidine decarboxylase (HDC), which catalyzes histidine decarboxylation in vivo to produce histamine, an endogenous biogenic amine, plus carbon dioxide. Inhibiting histamine production in the body is proposed to ameliorate symptoms of allergy and other diseases that result from high histamine production, such as rhinitis, dermatitis, eczema, urticaria, asthma, . . . . Tritoqualine has also been described in WO2008100539 for the treatment of gastrointestinal disease conditions ameliorated by histamine management, including Gastro-Esophageal Reflux Disease (GERD), a food allergy, Zollinger-Ellison Syndrome, peptic ulcer, dyspepsia, allergic eosinophilic gastroenteritis, and mastocytosis with gastrointestinal symptoms.
In the patent application US20100144718, tritoqualine (TRQ) (including derivatives or isomers thereof) is described as an histamine H4 receptor (H4R) agonist. The application further discloses the use of H4R agonists, such as TRQ, to treat diseases and/or disease conditions modulated by H4R agonists. The H4R modulated disease or condition is more particularly COPD and/or asthma.